Severely impaired urinary concentrating ability in transgenic mice lacking aquaporin-1 water channels.
Water channel aquaporin-1 (AQP1) is strongly expressed in kidney in proximal tubule and descending limb of Henle epithelia and in vasa recta endothelia. The grossly normal phenotype in human subjects deficient in AQP1 (Colton null blood group) and in AQP4 knockout mice has suggested that aquaporins (other than the vasopressin-regulated water channel AQP2) may not be important in mammalian physiology. We have generated transgenic mice lacking detectable AQP1 by targeted gene disruption. In kidney proximal tubule membrane vesicles from knockout mice, osmotic water permeability was reduced 8-fold compared with vesicles from wild-type mice. Although the knockout mice were grossly normal in terms of survival, physical appearance, and organ morphology, they became severely dehydrated and lethargic after water deprivation for 36 h. Body weight decreased by 35 +/- 2%, serum osmolality increased to >500 mOsm, and urinary osmolality (657 +/- 59 mOsm) did not change from that before water deprivation. In contrast, wild-type and heterozygous mice remained active after water deprivation, body weight decreased by 20-22%, serum osmolality remained normal (310-330 mOsm), and urine osmolality rose to >2500 mOsm. Urine [Na+] in water-deprived knockout mice was <10 mM, and urine osmolality was not increased by the V2 agonist DDAVP. The results suggest that AQP1 knockout mice are unable to create a hypertonic medullary interstitium by countercurrent multiplication. AQP1 is thus required for the formation of a concentrated urine by the kidney.
Ma
T
T
Department of Medicine, Cardiovascular Research Institute, University of California, San Francisco, California 94143-0521, USA.
Yang
B
B
Gillespie
A
A
Carlson
E J
EJ
Epstein
C J
CJ
Verkman
A S
AS
D000818:Animals; D051398:Aquaporin 1; D020346:Aquaporins; D003001:Cloning, Molecular; D007473:Ion Channels / Q000235:genetics*; D007687:Kidney Tubules, Proximal / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009994:Osmolar Concentration; D010539:Permeability; D014556:Urine
C496021:Aqp1 protein, mouse; D020346:Aquaporins; D007473:Ion Channels; D051398:Aquaporin 1